EP0141613B1 - Verfahren zur Herstellung eines optisch aktiven 3-(3,4-Dihydroxyphenyl)-Serins und ein geschütztes Derivat davon - Google Patents

Verfahren zur Herstellung eines optisch aktiven 3-(3,4-Dihydroxyphenyl)-Serins und ein geschütztes Derivat davon Download PDF

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EP0141613B1
EP0141613B1 EP84307297A EP84307297A EP0141613B1 EP 0141613 B1 EP0141613 B1 EP 0141613B1 EP 84307297 A EP84307297 A EP 84307297A EP 84307297 A EP84307297 A EP 84307297A EP 0141613 B1 EP0141613 B1 EP 0141613B1
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group
serine
dihydroxyphenyl
acyl
streptomyces
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EP0141613A3 (en
EP0141613A2 (de
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Hamao Umezawa
Tomio Takeuchi
Toshiharu Nagatsu
Masa Hamada
Shuichi Iwadare
Ikuo Matsumoto
Hajime Morishima
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Microbial Chemistry Research Foundation
MSD KK
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Microbial Chemistry Research Foundation
Banyu Phamaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
    • C12P7/26—Ketones
    • C12P7/38—Cyclopentanone- or cyclopentadione-containing products
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
    • C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/826—Actinomyces
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/886—Streptomyces
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/908—Streptovirticillium

Definitions

  • This invention relates to a process for the production of an optically active 3-(3,4-dihydroxyphenyl)-serine which is known to be useful as a medicine, or an optically active 3-(3,4-dihydroxyphenyl)serine protected derivative in which the catecholic 3- and 4-hydroxyl groups on the phenyl ring have been protected and which is useful as an intermediate product for the production of an optically active 3-(3,4-dihydroxyphenyl)-N-methylserine.
  • L-threo-3-(3,4-dihydroxyphenyl)serine (sometime referred to as L-threo-DOPS) is useful as an anti-depressant agent or anti-hypertensive agent (see Japanese patent application unexamined first publication "Kokai” No. 49252/75; Japanese patent application unexamined first publication "Kokai” No. 20747/80; U.S. Patent No. 3,920,728; U.S. Patent No. 4,319,040) and also as an anti-parkinsonian agent (see Japanese patent application unexamined first publication "Kokai" No. 125630/77).
  • L-erythro-3-(3,4-dihydroxyphenyl)serine is useful as an anti-hypertensive agent (see Japanese patent application unexamined first publication "Kokai" No. 49252/75). Further, such an L-threo-3-(3,4-dihydroxyphenyl)serine 0-protected derivative in which the catecholic hydroxyl groups present at the meta- and para-positions of the phenyl ring each have been protected with a known hydroxyl-protective group is useful as a starting material for synthesis of L-threo-3-(3,4-dihydroxyphenyl)-N-methylserine which is interesting as psychotropic agent, especially anti-depressant agent and as anti-parkinsonian agent (see Japanese patent application No.
  • an optically active that is, L- or D-threo-3-(3,4-dihydroxyphenyl)serine
  • an optically inactive that is, DL-threo-N-benzyloxycarbonyl-3-(3,4-dibenzyloxyphenyl)serine
  • optical resolution procedure using as the optically resolving agent an optically active ephedrine or an optically active threo-1-(p-nitrophenyl)-2-amino-1,3-propanediol
  • quinine see Japanese patent application unexamined first publication "Kokai” No. 65242/77
  • an optically active threo-1-(p-methylsulfonylphenyl)-2-amino-1,3-propanediol see Japanese patent application unexamined first publication "Kokai” No. 36233/79
  • optically active S-2-amino-1,1-diphenylpropanol, S-2-amino-3-methyl-1,1-diphenylbutanol or S-2-amino-4-methyl-1,1-diphenylpentanol see Japanese patent application unexamined first publication "Kokai" No.
  • the threo isomer or the erythro isomer of DL-3-(3,4-dihydroxyphenyl)serine as prepared by a known method, or such a DL-3-(3,4-dihydroxyphenyl)serine O-protected derivative having the catecholic 3- and 4-hydroxyl groups protected may be N-acylated with an alkanoyl group or an aroyl group in a known manner, and the N-acyl-DL-3-(3,4-dihydroxyphenyl)serine or the N-acyl-0-protected derivative thereof so produced may then be subjected to enzymatic reaction with a culture broth of a microorganism of the genus Streptomyces or the genus Streptoverticillium having the acylase, or with a material obtained from a treatment of said culture broth and containing the acylase, for example, the cells of the microorganism separated from said culture broth, and an enzyme material obtained from a treatment
  • the process of this invention may further include a step of removing the residual hydroxyl-protecting groups (R 1 , R 2 ) from the resulting L-3-(3,4-dihydroxyphenyl)serine 0-protected derivative of the formula (II) in a known manner to give L-3-(3,4-dihydroxyphenyl)serine, and/or a step of removing the N-acyl group (-CO-R 3 ) from the resulting N-acyl-D-3-(3,4-dihydroxyphenyl)serine compound of the formula (III), if necessary, followed by a further step of removing the residual hydroxyl-protecting groups (R 1 , R 2 ) from the resultant D-3-(3,4-dihydroxyphenyl)serine 0-protected derivative in a known manner to give D-3-(3,4-dihydroxyphenyl)serine.
  • N-acyl-D-3-(3,4-dihydroxyphenyl)serine compound of the formula (III) as obtained in accordance with the process of this invention is hydrolyzed by a chemical agent in a known manner for removal of the N-acyl group therefrom, there is produced D-3-(3,4-dihydroxyphenyl)serine or its 0-protected derivative having the catecholic 3- and 4-hydroxyl groups protected.
  • a process for de-acylating stereoselectively an N-acyl-L-3-(3,4-dihydroxyphenyl)serine compound of the formula (I') wherein R 1 , R 2 and R 3 are as defined above which process comprises reacting the N-acyl-L-3-(3,4-dihydroxyphenyl)serine compound (I') with a microorganism of the genus Streptomyces or the genus Streptoverticillium having an acylase capable of removing hydrolytically the N-acyl group ( ⁇ CO ⁇ R 3 ) preferentially from the N-acyl-L-serine compound (I'), or with an extract of said microorganism containing said acylase, to remove said N-acyl group from the N-acyl-L-serine compound (I') and thereby to produce the L-3-(3,4-dihydroxyphenyl)serine compound of the formula (II) wherein R
  • the microorganism which is used in accordance with this invention may be any strain belonging to the genus Streptomyces or the genus Streptoverticillium, as far as it is such microorganism which is capable of removing hydrolytically the N-acyl group (R 3 CO ⁇ ) selectively from the N-acyl-L-3-(3,4-dihydroxyphenyl)serine or a catecholic hydroxyl-protected derivative thereof which is present in the DL-serine compounds of the general formula (I) shown hereinbefore, or such microorganism which has or produces an acylase capable of removing hydrolytically said N-acyl group selectively from said N-acyl-L-3-(3,4-dihydroxyphenyl)serine or said catecholic hydroxyl-protected derivative thereof.
  • microorganisms which may conveniently be used in the process of this invention include the following species:- Streptomyces aureoverticillatus (IMC S-0234) (ISP 5080) (FERM P-7216) (ATCC 19726; CBS 465.68) (IFO 12742), Streptomyces bicolor (IMC S-0276) (ISP 5140) (ATCC 23614; CBS 469.68) (IFO 12746), Streptomyces blastmyceticus (IMC S-0189) (ISP 5029) (FERM P-7217) (ATCC 19731; CBS 470.68) (IFO 12747), Streptomyces chartreusis (IMC S-226) (ISP 5085) (ATCC 19738; CBS 476.68) (IFO 12753), Streptomyces flavopersicus (IMC S-0204) (ISP 5093) (ATCC 19756; CBS 494.68) (IFO 12769), Streptomyces flavotricini (IMC
  • the "IMC” numbers given to the above-mentioned microorganisms are the applicant's reference numerals of the cultures stored in the applicant's laboratory "Institute of Microbial Chemistry", Kami-Osaki, Meguro-ku, Tokyo, Japan.
  • the "ISP” numbers given to these microorganisms are the standard reference numerals alloted by "International Streptomyces Projects”.
  • the starting substrate compound of the formula (I) may be reacted with the microorganism as used in accordance with this invention, by being contacted with said microorganism which is present in the culture broth of said microorganism.
  • the microorganism is cultivated in a known manner using conventional culture media.
  • the carbon sources present in the culture medium used may be usual ones e.g. glucose, saccharose, fructose, mannose, starch, molasses and the like, and the nitrogen sources may be usual ones e.g.
  • the cultivation of the microorganism may preferably be carried out under aerobic conditions, e.g. by incubation under aeration and stirring. Preferred cultivation temperatures may be in a range of 20° to 40°C.
  • the cultivation duration may normally be in a range of 1 day to 10 days in many instances.
  • the microorganism used and the culture broth of the microorganism serve as the source for the acylase which participates in the enzymatic de-acylation reaction involved in the present process.
  • the cells which have been separated from the culture broth in the intact state which may be live or dead or which also have been immobilised in a manner known for the techniques for immobilisation of microbial cells.
  • the process of this invention may also be performed using an extract of said microorganism containing said acylase.
  • This acylase-containing extract of the microorganism may be in the form of such filtrate of the culture broth of the microorganism, such material obtained from treatment of the cells, particularly a cell homogenate wherein the acylase is existing, or a solution of the acylase which has been isolated in crude or pure form.
  • This solution of the acylase may be a solution of a crude enzyme (the acylase) which has been recovered from the culture broth or the cells of the microorganism by fractional precipitation method with ammonium sulfate, or a solution of a purified enzyme (the acylase) which has been purified by a gel-filtration method or other known purification method for enzymes.
  • the recovery and purification of the enzyme may be achieved according to any known method for preparing acylases.
  • N-acyl-DL-3-(3,4-dihydroxyphenyl)serine or a catecholic hydroxyl-protected derivative thereof according to the general formula (I) employed as the starting compound in the process of this invention may be prepared by reacting a carboxylic acid of the general formula (IV) wherein R 3 is as defined above, or a reactive derivative (a functional equivalent) thereof, such as the acid chloride and acid anhydride, in the presence or absence of a condensation agent or catalyst, with DL-3-(3,4-dihydroxyphenyl)serine which may be produced by previously known methods (see “J. Chem. Soc.” pp. 658-662 (1947); "J. Am. Chem. Soc.” 76, pp.
  • N-acyl group (R 3 C0-) as used may preferably be acetyl group, chloroacetyl group, glycolyl group, benzoyl group and the like, though any acyl group may be used in accordance with this invention as long as it is cleavable preferentially by the enzymatic reaction of the present process.
  • the starting N-acyl-DL-3-(3,4-dihydroxyphenyl)serine or a catecholic hydroxyl-protected derivative thereof according to the general formula (I) used as the starting compound contains two asymmetrical carbon atoms in the molecule thereof, so that there exist two isomers of the threo form and the erythro form.
  • the threo-isomer or the erythro-isomer or even a mixture of them may be employed as the starting substrate in the process of this invention.
  • the starting DL-serine compound of the general formula (I) which serves as the substrate in the enzymatic de-acylation reaction of the present process may either be protected or unprotected at its catecholic 3- and 4-hydroxyl groups on the phenyl ring, depending on the purposes for which the de-acylated product of the present process is utilized.
  • the catecholic hydroxyl groups of the substrate serine compound (I) may be unprotected.
  • the enzymatic reaction in the process of this invention may preferabry be conducted using the starting DL-serine compound of the general formula (I) in the form of the hydroxyl-protected derivative thereof, because the catecholic hydroxyl groups of the serine compound must have been protected for the subsequent N-methylation process.
  • an optically active 3-(3,4-dihydroxyphenyl)serine can, of course, be obtained readily by removing the hydroxyl-protecting groups from the de-acylated product by a conventional deprotection technique after the enzymatic reaction of the present process was achieved.
  • the hydroxyl-protecting groups (R 1 , R 2 ) available for protection of the catecholic 3- and 4-hydroxyl groups of the starting N-acyl-DL-serine compound (I) may be any of the hydroxyl-protecting groups which are conventionally employed for blocking the catecholic hydroxyl groups, for example, an aralkyl group such as benzyl, an alkoxycarbonyl group such as ethoxycarbonyl, an alkylidene group such as methylene and isopropylidene, or a cycloalkylidene group such as cyclohexylidene. A most preferred one is benzyl group.
  • the enzymatic reaction of reacting the starting N-acyl-DL-serine compound of the formula (I) with the microorganism or the acylase of said microorganism may preferably be carried out at a pH of 5 to 9, desirably at a pH of 6 to 5 and at a temperature of 20 to 80°C, desirably 35° to 60°C.
  • the reaction medium may be water not containing or containing, if necessary, a proportion of an organic solvent which does not inactivate the enzyme, such as a lower alkanol, e.g. ethanol.
  • the enzymatic reaction may be conducted in the presence of cation of a metal such as cobalt as the catalyst added.
  • the required reaction time may vary depending on the quantity and the activity of the enzyme used, the reaction temperature and other various factors, but normally the reaction may be conducted for a time of 30 minutes to 20 hours. A reaction time of 2 hours to 18 hours will suffice in many cases.
  • the step of the enzymatic reaction may be followed by the step of separating the resultant L-3-(3,4-dihydroxyphenyl)serine or the catecholic hydroxyl-protected derivative thereof according to the general formula (II) from the N-acyl-D-3-(3,4-dihydroxyphenyl)serine or the catecholic hydroxyl-protected derivative thereof according to the general formula (III) which remains without receiving the enzymatic de-acylation.
  • This separation may be performed by a precipitation method utilizing the fact that generally, the N-acyl-D-3-(3,4-dihydroxyphenyl)serine compounds are less soluble than the L-3-(3,4-dihydroxyphenyl)-serine compounds in an aqueous medium at acidic pH range.
  • the separation of the L-serine compound (II) from the N-acyl-D-serine compound (III) may be achieved by a transfer-dissolution method, as illustrated by Example 2 given later, in such a manner that the enzymatic reaction solution is extracted with n-butanol to afford a solution of both the L-compounds of the formula (II) and the D-compound of the formula (111) in n-butanol, the n-butanol is evaporated off from said solution, the resultant residue is taken up into 0.05 M phosphate buffered solution (pH 7.0), the resulting solution containing the compounds (II) and (III) is adjusted to acidic pH with hydrochloric acid and then extracted with ethyl acetate to transfer mainly the compound (III) into ethyl acetate, the ethyl acetate extract is in turn, extracted with alkaline water (pH 9) to transfer the compound (III) into the aqueous
  • the final products (II) and (III) as obtained by the process of this invention each may further be isolated and purified by an ordinary chromatographic method such as silica gel column chromatography and ionexchange resin chromatography. It is also possible to make isolation and purification of the final products in a very easy way e.g. by precipitation method or crystallization method with utilizing the difference in the solubilities of these products (II), (III).
  • the solution of the substrate (0.5 ml) was mixed with 0.5 ml of the enzyme solution which was prepared according to the procedure of Example 1(a) and which was containing the acylase of the microorganism, Streptomyces hachijoensis.
  • the mixture so obtained was incubated at 37°C for 17 hours for the enzymatic reaction to effect the removal of the N-acyl group (the de-acylation) from the substrate compound.
  • the culture medium of the same composition as used in Example 1 was inoculated with a loopful quantity of a slant culture of Streptomyces aureoverticillatus (IMC S-0234) (ISP 5080) (FERM P-7216) (FERM BP-640); Streptomyces blastmyceticus (IMC S-0189) (ISP 5029) (FERM P-7217) (FERM BP-641); or Streptomyces hachijoensis (IMC S-0244) (ISP 5114) (FERM P-7218) (FERM BP-642), and the shaken incubation was made at 27°C for 4 days.
  • the culture broth obtained was filtered to remove the microbial cells, and the resultant broth filtrate (0.5 ml) containing the acylase was mixed with 0.5 ml of the substrate solution comprising a solution containing DL-threo-N-acetyl-3-(3,4-dibenzyloxyphenyl)serine at a concentration of 2 mg/ml in 0.1 M phosphate buffered solution (pH 7.0). The mixture was incubated at 37°C for 17 hours to effect the enzymatic reaction.
  • the reaction mixture was made acidic by addition of 0.1 ml of 1 N hydrochloric acid and then extracted with two 1 ml-portions of n-butanol.
  • the combined extracts in n-butanol were distilled under reduced pressure to remove the n-butanol.
  • the residue was dissolved in 1 ml of a mixture of 0.1 M phosphoric acid and methanol (40:60 by volume), and the resultant solution was analysed by a high performance liquid chromatography with the same "Nucleosil 5 C 18 "® column as used in Example 3, to determine the yield of the de-acylation product as formed, namely the L-threo-3-(3,4-dibenzyloxyphenyl)serine.
  • Example 4 The procedures of Example 4 were repeated but using the other strains. The results obtained are summarized in Table 3 below.

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Claims (7)

1. Verfahren zur Herstellung einer optisch aktiven L-3-(3,4-Dihydroxyphenyl) Serin-Verbindung mit der Formel (ll)
Figure imgb0022
worin R1 und R2 jeweils ein Wasserstoffatom oder eine Hydroxyl-Schutzgruppe für die Katechin 3- und 4-Hydroxylgruppen am Phenylring ist, und einer optisch aktiven D-3-(3,4-Dihydroxyphenyl) Serin-Verbindung mit der Formel (lll)
Figure imgb0023
worin R1 und R2 wie oben definiert sind und R3 eine nichtsubstituierte oder substituierte Alkylgruppe oder eine nichtsubstituierte oder substituierte Arylgruppe ist, dadurch gekennzeichnet, daß eine N-Acyl-DL-3-(3,4-Dihydroxyphenyl) Serin-Verbindung mit der allgemeinen Formel (I)
Figure imgb0024
worin R1, R2 und R3 wie oben definiert sind, mit einem Mikroorganismus der Gattung Streptomyces oder der Gattung Streptoverticillium zur Reaktion gebracht wird, der eine Acylase enthält, welche in der Lage ist, die N-Acylgruppe (-CO-R3) hydrolytisch vorzugsweise vom L-Isomer der DL-Serin-Verbindung nach Formel (l) zu trennen, oder mit einem Extrakt dieses Mikroorganismus, der diese Acylase enthält, um vorzugsweise die N-Acylgruppe (-CO-R3) von der Aminogruppe des in der DL-Serin-Verbindung nach Formel (l) vorhandenen L-Isomers zu trennen und dadurch die L-3-(3,4-Dihydroxyphenyl) Serin-Verbindung nach Formel (ll) zu erzeugen, und daß diese L-Serin-Verbindung (ll) von der N-Acyl-D-3-(3,4-Dihydroxyphenyl) Serin-Verbindung nach Formal (lll) getrennt wird, welche unverändert bleibt, ohne entacyliert zu werden.
2. Verfahren zum stereoselektiven Entacylieren einer N-Acyl-L-3-(3,4-Dihydroxyphenyl) Serin-Verbindung nach der Formel (1')
Figure imgb0025
worin R1 und R2 jeweils ein Wasserstoffatom oder eine Hydroxyl-Schutzgruppe für die Katechin 3- und 4-Hydroxylgruppen am Phenylring und R3 eine nichtsubstituierte oder substituierte Alkylgruppe oder eine nichtsubstituierte oder substituierte Arylgruppe ist, dadurch gekennzeichnet, daß die N-Acyl-L-3-(3,4-Dihydroxyphenil) Serin-Verbindung (l') mit einem Mikroorganismus der Gattung Streptomyces oder der Gattung Streptoverticillium zur Reaktion gebracht wird, der eine Acylase enthält, welche in der Lage ist, die N-Acylgruppe (―CO―R3) hydrolytisch vorzugsweise von der N-Acyl-L-Serin-Verbindung (I') zu-trennen, oder mit einem Extrakt dieses Mikroorganismus, der diese Acylase enthält, um diese N-Acylgruppe von der N-Acyl-L-Serin-Verbindung (I') zu trennen und dadurch die L-3-(3,4-Dihydroxyphenyl) Serin-Verbindung nach Formel (ll) zu erzeugen,
Figure imgb0026
worin R1 und R2 wie oben definiert sind.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß die Hydroxyl-Schutzgruppen R1 und R2 jeweils unabhängig voneinander eine Benzylgruppe darstellen und R3 eine Methylgruppe, eine Chlormethylgruppe, eine Hydroxymethylgruppe oder eine Phenylgruppe darstellt.
4. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß. die Hydroxyl-Schutzgruppen R1 und R2 zusammengenommen eine einzige Alkylengruppe (alkylidene group) wie z.B. eine Methylengruppe oder eine Zykloalkylengruppe darstellen und R3 eine Methylgruppe, eine Chlormethylgruppe, eine Hydroxymethylgruppe oder eine Phenylgruppe darstellt.
5. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß R1 und R2 jeweils unabhängig voneinander ein Wasserstoffatom und R3 eine Methylgruppe, eine Chlormethylgruppe, eine Hydroxymethylgruppe oder eine Phenylgruppe darstellt.
6. Verfahren nach einem der vorangehenden Ansprüche, dadurch' gekennzeichnet, daß der Mikroorganismus Streptomyces aureoverticallatus (ATCC 19726 oder FERM BP-640), Streptomyces bicolor (ATCC 23614), Streptomyces blastmyceticus (ATCC 19731 oder FERM BP-641) Streptomyces chartreusis (ATCC 19738), Streptomyces flavopersicus (ATCC 19756), Streptomyces flavotricini (ATCC 23621), Streptoverticillium griseocarneum (ATCC 19763), Streptomyces hachijoensis (ATCC 19769 oder FERM BP-642), Streptomyces halstedü (ATCC 19770), Streptoverticillium hiroshimense (ATCC 19772 oder FERM BP-643), Streptomyces tendae (ATCC 19812), und Streptomyces toyocaensis (ATCC 19814 oder FERM BP-644) ist.
7. Verfahren nach einem der vorangehenden Ansprüche, dadurch gekennzeichnet, daß die Reaktion einer N-Acyl-DL-3-(3,4-Dihydroxyphenyl) Serin-Verbindung nach Formel (I) mit dem Mikroorganismus oder dem Extrakt des Mikrooranismus, der die Acylase enthält, bei einer Temperatur von 20° bis 80°C, mit einem pH-Wert von 5 bis 9 und über eine Dauer von 30 Minuten bis 20 Stunden durchgeführt wird.
EP84307297A 1983-11-04 1984-10-24 Verfahren zur Herstellung eines optisch aktiven 3-(3,4-Dihydroxyphenyl)-Serins und ein geschütztes Derivat davon Expired EP0141613B1 (de)

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AT84307297T ATE40570T1 (de) 1983-11-04 1984-10-24 Verfahren zur herstellung eines optisch aktiven 3-(3,4-dihydroxyphenyl)-serins und ein geschuetztes derivat davon.

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JP58205859A JPS6098995A (ja) 1983-11-04 1983-11-04 光学活性３−（３，４−ジヒドロキシフエニル）セリン，およびその誘導体の製造法
JP205859/83 1983-11-04

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EP0141613A3 EP0141613A3 (en) 1985-09-11
EP0141613B1 true EP0141613B1 (de) 1989-02-01

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US5707836A (en) * 1995-03-10 1998-01-13 Nitto Chemical Industry Co., Ltd. Production of alkylene or phenylenediamine disuccinic acid from fumaric acid and a diamine using lyase from microbes
CA2388050C (en) * 1999-08-12 2008-03-18 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Antibiotic caprazamycins and process for producing the same
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JP2005278401A (ja) * 2002-09-09 2005-10-13 Nippon Kayaku Co Ltd 光学活性−エリスロ−３−シクロヘキシルセリンの製造方法
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Also Published As

Publication number Publication date
HU193234B (en) 1987-08-28
EP0141613A3 (en) 1985-09-11
DE3476560D1 (en) 1989-03-09
JPH0559719B2 (de) 1993-08-31
CA1241612A (en) 1988-09-06
KR850003572A (ko) 1985-06-20
JPS6098995A (ja) 1985-06-01
HUT38393A (en) 1986-05-28
US4699879A (en) 1987-10-13
ATE40570T1 (de) 1989-02-15
EP0141613A2 (de) 1985-05-15

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